“Alzheimer's disease” or “AD” is a neurodegenerative disease of the central nervous system associated with progressive memory loss. It is the most common form of senile dementia. It constitutes the 6th cause of death in the USA. 5.3 million people currently live with the disease in the USA for a global annual healthcare cost of $148 billion. In France 0.85 million people are currently diagnosed with AD. In extended European countries, including Turkey, 10.11 million patients are affected by the disease for a global annual healthcare cost of € 177 billion. The number of people affected with AD is expected to nearly double every two decades to reach 65.7 million in 2030 and 115.4 million in 2050 worldwide.
Current treatments only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. Alzheimer's disease is non-curable. The disease worsens as it progresses, patients progressively losing all autonomy, and ultimately leads to death. On average, the life expectancy following diagnosis is approximately seven years. Fewer than 3% of individuals live more than 14 years after diagnosis (Mölsä et al.; 1995).
In developed countries, AD is one of the most costly diseases to society (Bonin-Guillaume et al.; 2005). In 2006, there were 26.6 million people worldwide with AD. Alzheimer's is predicted to affect 1 in 85 people globally by 2050 (Brookmeyer et al.; 2007).
The cause and progression of the disease are not well understood. It is associated with extracellular plaques and intracellular tangles in areas of the brain essential for cognitive function (Tiraboschi et al.; 2004). Plaques are formed mostly from the deposition of amyloid beta (“Aβ”), a peptide derived from amyloid precursor protein (“APP”). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorylated tau protein, a microtubule-associated protein. It is not clear however whether these two pathological changes are only associated with the disease or truly involved in the degenerative process.
Diagnosis of AD is long and difficult because of the lack of sensitivity of the neurological examination used in the clinic. AD develops for an unknown and variable amount of time before becoming fully apparent, and it can progress undiagnosed for years. The early stages of Alzheimer's disease are in particular very difficult to diagnose. Early symptoms are indeed often mistakenly thought to be ‘age-related’ concerns or manifestations of stress (Waldemar et al.; 2007) and predicting how the disease will affect a person is difficult. In the early stages, the most common symptom is difficulty in remembering recent events, known as short term memory loss.
A more accurate diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. When AD is suspected, the diagnosis is usually refined with tests that evaluate behaviour and thinking abilities, often followed by a brain scan if available. Brain scan (CT, MRI, PET and/or SPECT scans and EEG) can indeed help excluding other cerebral pathology or subtypes of dementia.
The symptoms will progress from mild cognitive impairments (“MCI”), such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease (Forstl et al.; 1999). As the disease advances, symptoms can include confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss. As the person's condition declines they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death.
US 2010/124756 indicates that the respective levels of at least 16 circulating biomarkers are to be measured in a biological fluid sample from an individual for aiding in the diagnosis of AD and lMCI. WO2007/059135 describes methods for aiding in the diagnosis of AD and lMCI comprising detecting, measuring and/or identifying one or more of the biomarkers selected in a list comprising M-CSF and CCL18 (PARC) among other biomarkers which are not identified as relevant in the context of the present invention. As herein demonstrated by inventors, and contrary to the teaching of US 2010/124756, WO2007/059135, Laske C. et al. and Olson L. et al., the concentrations of M-CSF, CCL18 and RANTES do not linearly increase with disease progression.
Known markers for AD capable of supporting medical diagnostic at a validated stage of development include Amyloid Beta peptidic fragment 1-40 and 1-42 in blood or cerebrospinal fluid (CSF), genetic variants of the APOe4 gene, and phosphorylation status of Tau protein in CSF (cf. Laske C. et al for example). Despite a recent IVD (In Vitro Diagnostic) marking, these markers have failed to significantly penetrate the clinical practice because of the lack of robustness and reproducibility of the assays proposed. Data interpretation remains difficult and the field diverges on the actual clinical value of such markers, which remain marginally used in early stages of the disease. Diagnosis is thus mainly based on clinical criteria as well as on exclusion of other causes of dementia but a definitive diagnosis can only be made at autopsy when brain material is available and can be examined histologically.
Despite tremendous efforts and success in the development of medical imaging tools, diagnosing AD at an early stage remains a challenge. Undetected impairment in cognition has been associated with greater morbidity and mortality (Inouye et al., 2001), therefore, recognizing as early as possible the presence of impairment in cognitive functioning is becoming a crucial issue.
In addition, all drugs developed to date for AD have failed to show significant reduction in the progression rate or severity of the disease. A major impediment to the therapeutic development and clinical trial design for AD is again the lack of a sensitive, easily-obtained biomarker of disease state (O'Bryant et al., 2014, Henriksen et al., 2014, Thal et al., 2006 and Schneider et al., 2009). Recognizing the disease at an earlier stage when pathophysiological impairments have begun but their clinical manifestation is still silent will enhance the possibility for drugs targeting these mechanisms to show clinical benefit to the patient by retarding or stopping disease progression.
Furthermore, the capability to stratify patients in more homogeneous subgroups, in particular SCI, MCI and AD, will simplify clinical trials currently burdened by a highly heterogeneous patient population with the ability to design adaptive clinical trials, likely to reduce costs and length for obtaining clinical proof of concept (Chen et al., 2012).
The present invention now provide for the first time a blood protein panel to efficiently diagnose dementia, in particular Alzheimer's disease, at stages where it is not clinically expressed and in the early stages of its clinical expression.